Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition.

The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anticancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR-targeted therapies in cancer have seen limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of mTOR in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the mTOR loss, mTOR-/- HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II, which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite the loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a mechanism of evasive resistance in the context of mTOR targeting.

The chromatin remodeler CHD8 governs hematopoietic stem/progenitor survival by regulating ATM-mediated P53 protein stability.

The Chd8 gene encodes a member of the chromodomain helicase DNA-binding (CHD) family of SNF2H-like adenosine triphosphate (ATP)-dependent chromatin remodeler, the mutations of which define a subtype of autism spectrum disorders. Increasing evidence from recent studies indicates that ATP-dependent chromatin-remodeling genes are involved in the control of crucial gene-expression programs in hematopoietic stem/progenitor cell (HSPC) regulation. In this study, we identified CHD8 as a specific and essential regulator of normal hematopoiesis. Loss of Chd8 leads to severe anemia, pancytopenia, bone marrow failure, and engraftment failure related to a drastic depletion of HSPCs. CHD8 forms a complex with ATM and its deficiency increases chromatin accessibility and drives genomic instability in HSPCs causing an activation of ATM kinase that further stabilizes P53 protein by phosphorylation and leads to increased HSPC apoptosis. Deletion of P53 rescues the apoptotic defects of HSPCs and restores overall hematopoiesis in Chd8-/- mice. Our findings demonstrate that chromatin organization by CHD8 is uniquely necessary for the maintenance of hematopoiesis by integrating the ATM-P53-mediated survival of HSPCs.

The Association of Antimicrobial Prophylaxis With Return Visits After Dog Bites in Children.

OBJECTIVES: Dog bites occur frequently in the United States, yet there are no clear guidelines for prescribing antibiotic prophylaxis in healthy children after a dog bite. The aim of our study was to assess antibiotic prophylaxis and subsequent rates of infection after dog bites in children. We hypothesized a negative association between prophylactic prescription of any antimicrobial and return visit within 14 days for infection. METHODS: In this retrospective cohort study, we assessed the frequency of antibiotic prophylaxis prescribed after dog bite injuries in patients 0 to 18 years old and subsequent return visits for infection using 2016 to 2017 medical and pharmacy claims derived from the IBM MarketScan Research Databases. We used the International Classification of Diseases-10 code W54 for dog bites then used keyword searches to find diagnoses (including infection), wound descriptions, and medications. RESULTS: Over the 2-year period, 22,911 patients were seen for dog bites that were not coded as infected. The majority, 13,043 (56.9%), were prescribed an antibiotic at the initial visit and 9868 (43.1%) were not. Of those prescribed antibiotics, 98 (0.75%; 95% confidence interval [CI], 0.60-0.90) returned with an infection, compared with 59 (0.60%; 95% CI, 0.44-0.75) of those not prescribed antibiotics. Receiving an antibiotic prescription at the initial visit was associated with a reduced rate of return for wound infection only among children whose wounds were repaired or closed. Children not receiving a prescription whose wounds were repaired were more than twice as likely to return with an infection in the subsequent 14 days as children whose wounds were not repaired (odds ratio, 2.2; 95% CI, 1.2-4.0). CONCLUSIONS: Most children are prescribed antibiotics at an initial emergency department visit after a dog bite. However, very few return for infection independent of antimicrobial prophylaxis, which suggests antibiotics are overprescribed in this setting.

Pharmacotherapy for Treatment of Tobacco Use Disorder.

Tobacco use disorder (TUD), the leading cause of preventable deaths in the United States, disproportionally impacts those with psychiatric disorders. There are multiple first-line, U.S. Food and Drug Administration-approved pharmacotherapy options for the treatment of TUD. The current review focuses on these medications, underlining practical tips to improve cessation rates, while emphasizing a harm reduction and patient-centered approach to treatment. [Journal of Psychosocial Nursing and Mental Health Services, 61(11), 6-9.].

Cationic Glycopolyelectrolytes for RNA Interference in Tick Cells.

The black-legged tick (Ixodes scapularis) is the primary vector for bacteria that cause Lyme disease (Borrelia burgdorferi), where numerous glycosylated tick proteins are involved at the interface of vector-host-pathogen interactions. Reducing the expression of key tick proteins, such as selenoprotein K (SelK), through RNA interference is a promising approach to reduce pathogen transmission, but efficient delivery of nucleic acids to arthropods has proven challenging. While cationic glycopolymers have been used as nonviral gene delivery vehicles in mammalian cells, their use in arthropod or insect gene transfection has not been established. In this study, statistical acrylamide-based cationic glycopolymers with glucose or galactose pendant groups were synthesized by reversible addition-fragmentation chain transfer polymerization, and the effects of the saccharide pendant group and cationic monomer loading on polymer cytotoxicity, RNA complexation, and SelK gene knockdown in ISE6 cells were evaluated. All polymers exhibited low cytotoxicity, yet RNA/copolymer complex cell uptake and gene knockdown were highly dependent on the saccharide structure and the N:P (amino to phosphate groups) ratio.

Seedling responses to soil moisture amount versus pulse frequency in a successfully encroaching semi-arid shrub.

Rainfall timing, frequency, and quantity is rapidly changing in dryland regions, altering dryland plant communities. Understanding dryland plant responses to future rainfall scenarios is crucial for implementing proactive management strategies, particularly in light of land cover changes concurrent with climate change. One such change is woody plant encroachment, an increasing abundance of woody plants in areas formerly dominated by grasslands or savannas. Continued woody plant encroachment will depend, in part, on seedling capacity to establish and thrive under future climate conditions. Seedling performance is primarily impacted by soil moisture conditions governed by precipitation amount (quantity) and frequency. We hypothesized that (H1) seedling performance would be enhanced by both greater soil moisture and pulse frequency, such that seedlings with similar mean soil moisture would perform best under high pulse frequency. Alternatively, (H2) mean soil moisture would have greater influence than pulse frequency, such that a given pulse frequency would have little influence on seedling performance. The hypotheses were tested with Prosopis velutina, a shrub native to the United States that has encroached throughout its range and is invasive in other continents. Seedlings were grown in a greenhouse under two soil moisture treatments, each which was maintained by two pulse frequency treatments. Contrary to H1, mean soil moisture had greater impact than pulse frequency on seedling growth, photosynthetic gas exchange, leaf chemistry, and biomass allocation. These results indicate that P. velutina seedlings may be more responsive to rainfall amount than frequency, at least within the conditions seedlings experienced in this experimental manipulation.

Oral Aspirin/ketamine versus oral ketamine for emergency department patients with acute musculoskeletal pain.

OBJECTIVE: The purpose of this study is to investigate if an orally administered combination of aspirin and ketamine will provide better analgesia than a ketamine alone in adult patients presenting to the Emergency Department (ED) with acute musculoskeletal pain. METHODS: We conducted a prospective, randomized, open-label trial of ED patients aged 18 and older presenting with moderate to severe acute musculoskeletal pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5. Patients were randomized to receive either 324 mg of VTS-Aspirin™ and 0.5 mg/kg of oral ketamine (AOK) that is directly swallowed or 0.5 mg/kg of oral ketamine (OK) alone that is swished first and then swallowed. Patients were assessed at baseline, 30, 60, 90, and 120 min. The primary outcome was a difference in pain scores between the two groups at 60 min post-administration. Secondary outcomes included adverse events and the need for rescue analgesia. RESULTS: We enrolled 60 patients in the study (30 per group). The difference in mean pain scores at 60 min between the AOK and OK groups was 2.6 [95% CI: 1.38-3.77] showing a lower mean pain score in the OK group. At 60 min, the AOK group had a change in mean pain score from 8.4 to 6.3 (difference 2.1; 95% CI: 1.35-3.00). The OK group had a change in mean pain score from 7.8 to 3.7 (difference 4.1, 95% CI: 3.25-4.90). No clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. The most commonly reported adverse effects were dizziness and fatigue. None of the participants required rescue analgesia at 60 min post-medications administration. CONCLUSION: The administration of an oral combination of VTS-Aspirin ™ and ketamine resulted in less analgesia compared to oral ketamine alone, for the short-term treatment of moderate to severe acute musculoskeletal pain in the ED. CLINICALTRIALS: govRegistration: NCT04860804.

Does Medialization Improve Swallowing Function in Patients with Unilateral Vocal Fold Paralysis? A Systematic Review.

Glottal incompetence caused by unilateral vocal fold paralysis (UVFP) is a common cause of dysphagia and aspiration. Treatments targeted at reducing glottal incompetence by injection augmentation or medialization thyroplasty are well established at improving voice outcomes, but improvements in swallowing function are less clear. The objective of this systematic review was to determine the impact of vocal fold medialization on dysphagia outcomes. Six electronic bibliographic databases and one clinical trial registry were searched on 3/13/2020. Our patient population were adult patients with verified UVFP that underwent vocal fold medialization. We limited review to prospective studies that had formal dysphagia assessment both before and after medialization. Nine studies met selection criteria (7 prospective case series and 2 prospective cohort studies) totaling 157 patients. The most common etiology of UVFP was iatrogenic (74/157; 47%). The majority of patients underwent injection augmentation (92/157; 59%), and the remaining underwent medialization thyroplasty. A variety of methods were used to assess changes in dysphagia including patient-reported outcome measures, flexible endoscopic evaluation of swallowing, videofluoroscopic swallow study, and high-resolution manometry. 7/9 studies demonstrated clinically significant improvement in swallowing function following medialization; 4/9 studies demonstrated statistically significant improvement, and three studies did not show statistically significant improvement after intervention. Study participants and outcome measures evaluating swallowing function in this review were heterogeneous. Moreover, the reviewed studies are concerning for multiple risks of bias impacting their conclusions. Taken together, this systematic review demonstrates limited evidence that injection augmentation and medialization thyroplasty improve swallowing function and/or safety.

Analgesic Efficacy of Oral Aspirin/Ketamine Combination for Management of Acute Musculoskeletal Pain in the Emergency Department - A Proof of Concept Pilot Study.

BACKGROUND: Musculoskeletal pain (MSK) affects one out of three adults and is the most common source of significant long-term pain, physical disability, and under-treatment in the emergency department (ED). OBJECTIVE: We aimed to assess the analgesic efficacy of a combination of oral VTS-Aspirin® (Vitalis Analgesics, New York, NY) and ketamine in managing acute MSK pain in adult ED patients. METHODS: This was a prospective, proof-of-concept, single-arm, pilot study evaluating the analgesic efficacy of a single dose of oral combination of VTS-Aspirin and ketamine in adult ED patients with acute moderate-to-severe MSK pain. The primary outcome included the difference in pain scores on an 11-point numeric pain rating scale at 60 min. Secondary outcomes included the need for rescue analgesia, the occurrence of adverse events at 60 min, and a change in pain scores at 120 min. RESULTS: We enrolled 25 subjects in the study. The mean baseline pain score was 8.6 and the mean pain score at 60 min decreased to 4.8. The oral ketamine dose ranged from 24 mg to 50 mg, with a mean dose of 37.8 mg. No clinically concerning changes in vital signs were noted. No serious adverse events occurred in any of the subjects. Majority of adverse effects were transient and weak in intensity. CONCLUSION: We demonstrated that administration of an oral combination of VTS-Aspirin and ketamine to adult ED patients with acute MSK pain resulted in clinically significant pain relief in 80% of enrolled subjects.

Paraphimosis Pain Treatment with Nebulized Ketamine in the Emergency Department.

BACKGROUND: Paraphimosis is an acute urological emergency occurring in uncircumcised males that can lead to strangulation of the glans and painful vascular compromise. Ketamine has been used in the emergency department (ED) as an anesthetic agent for procedural sedation, and when administrated in a sub-dissociative dose (low dose) at 0.1-0.3 mg/kg, ketamine has been utilized in the ED and prehospital settings for pain control as an adjunct and as an alternative to opioid, as well as for preprocedural sedation. This report details the case of a pediatric patient who presented to our Pediatric ED with paraphimosis and had his procedural pain treated with ketamine administrated via a breath-actuated nebulizer (BAN). CASE REPORT: This case report illustrates the potential use of ketamine via BAN to effectively achieve minimal sedation for a procedure in pediatric patients in the ED. The patient was a 15-year-old boy admitted to the Pediatric ED complaining of groin pain due to paraphimosis. The patient was given 0.75 mg/kg of nebulized ketamine via BAN, and 15 min after the medication administration the pain score was reduced from 5 to 1 on the numeric pain rating scale. The patient underwent a successful paraphimosis reduction without additional analgesic or sedative agents 20 min after the administration of nebulized ketamine. The patient was subsequently discharged home after 60 min of monitoring, with a pain score of 0. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The use of nebulized ketamine via BAN might represent a viable, noninvasive way to provide a mild sedative and be an effective analgesic option for managing a variety of acute painful conditions and procedures in the pediatric ED.

Skeletal muscle extracellular matrix remodeling with worsening glycemic control in nonhuman primates.

Type 2 diabetes (T2D) development may be mediated by skeletal muscle (SkM) function, which is responsible for >80% of circulating glucose uptake. The goals of this study were to assess changes in global- and location-level gene expression, remodeling proteins, fibrosis, and vascularity of SkM with worsening glycemic control, through RNA sequencing, immunoblotting, and immunostaining. We evaluated SkM samples from health-diverse African green monkeys (Cholorcebus aethiops sabaeus) to investigate these relationships. We assessed SkM remodeling at the molecular level by evaluating unbiased transcriptomics in age-, sex-, weight-, and waist circumference-matched metabolically healthy, prediabetic (PreT2D) and T2D monkeys (n = 13). Our analysis applied novel location-specific gene differences and shows that extracellular facing and cell membrane-associated genes and proteins are highly upregulated in metabolic disease. We verified transcript patterns using immunohistochemical staining and protein analyses of matrix metalloproteinase 16 (MMP16), tissue inhibitor of metalloproteinase 2 (TIMP2), and VEGF. Extracellular matrix (ECM) functions to support intercellular communications, including the coupling of capillaries to muscle cells, which was worsened with increasing blood glucose. Multiple regression modeling from age- and health-diverse monkeys (n = 33) revealed that capillary density was negatively predicted by only fasting blood glucose. The loss of vascularity in SkM co-occurred with reduced expression of hypoxia-sensing genes, which is indicative of a disconnect between altered ECM and reduced endothelial cells, and known perfusion deficiencies present in PreT2D and T2D. This report supports that rising blood glucose values incite ECM remodeling and reduce SkM capillarization, and that targeting ECM would be a rational approach to improve health with metabolic disease.

Differential weight loss with intermittent fasting or daily calorie restriction in low- and high-fitness phenotypes.

NEW FINDINGS: What is the central question of this study? How does intrinsic aerobic capacity impact weight loss with 50% daily caloric restriction and alternate-day fasting? What is the main finding and its importance? Intermittent fasting is effective for weight loss in rats with low fitness, which highlights the importance of how intermittent fasting interacts with aerobic fitness. ABSTRACT: Recent interest has focused on the benefits of time-restricted feeding strategies, including intermittent fasting, for weight loss. It is not yet known whether intermittent fasting is more effective than daily caloric restriction at stimulating weight loss and how each is subject to individual differences. Here, rat models of leanness and obesity, artificially selected for intrinsically high (HCR) and low (LCR) aerobic capacity, were subjected to intermittent fasting and 50% calorie restrictive diets in two separate experiments using male rats. The lean, high-fitness HCR and obesity-prone, low-fitness LCR rats underwent 50% caloric restriction while body weight and composition were monitored. The low-fitness LCR rats were better able to retain lean mass than the high-fitness HCR rats, without significantly different proportional loss of weight or fat. In a separate experiment using intermittent fasting in male HCR and LCR rats, alternate-day fasting induced significantly greater loss of weight and fat mass in LCR compared with HCR rats, although the HCR rats had a more marked reduction in ad libitum daily food intake. Altogether, this suggests that intermittent fasting is an effective weight-loss strategy for those with low intrinsic aerobic fitness; however, direct comparison of caloric restriction and intermittent fasting is warranted to determine any differential effects on energy expenditure in lean and obesity-prone phenotypes.

Comparison of Nebulized Ketamine at Three Different Dosing Regimens for Treating Painful Conditions in the Emergency Department: A Prospective, Randomized, Double-Blind Clinical Trial.

STUDY OBJECTIVE: We aimed to assess and compare the analgesic efficacies and adverse effects of ketamine administered through a breath-actuated nebulizer at 3 different dosing regimens for emergency department patients presenting with acute and chronic painful conditions. METHODS: This was a prospective, randomized, double-blinded trial comparing 3 doses of nebulized ketamine (0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg) administered through breath-actuated nebulizer in adult emergency department patients aged 18 years and older with moderate to severe acute and chronic pain. The primary outcome included the difference in pain scores on an 11-point numeric rating scale between all 3 groups at 30 minutes. Secondary outcomes included the need for rescue analgesia (additional doses of nebulized ketamine or intravenous morphine) and adverse events in each group at 30 and 60 minutes. RESULTS: We enrolled 120 subjects (40 per group). The difference in mean pain scores at 30 minutes between the 0.75 mg/kg and 1 mg/kg groups was 0.25 (95% confidence interval [CI] 1.28 to 1.78); between the 1 mg/kg and 1.5 mg/kg groups was -0.225 (95% CI -1.76 to 1.31); and between the 0.75 mg/kg and 1.5 mg/kg groups was 0.025 (95% CI -1.51 to 1.56). No clinically concerning changes in vital signs occurred. No serious adverse events occurred in any of the groups. CONCLUSION: We found no difference between all 3 doses of ketamine administered through breath-actuated nebulizer for short-term treatment of moderate to severe pain in the emergency department.

Analgesic efficacy of morphine sulfate immediate release vs. oxycodone/acetaminophen for acute pain in the emergency department.

OBJECTIVE: Previous research demonstrated that administration of Morphine Sulfate Immediate Release (MSIR) results in similar analgesic efficacy to Oxycodone but with significantly lesser degrees of euphoria and reward. The purpose of this study sit to investigate if MSIR combined with Acetaminophen can serve as an opioid analgesic alternative to Oxycodone combined with acetaminophen (Percocet) for acute pain in the Emergency Department (ED). METHODS: A prospective, randomized, double-blind trial of ED patients aged 18 to 64 years presenting with moderate to severe acute pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5 (0 = no pain and 10 = very severe pain). Patients were randomized to receive either 15 mg MSIR combined with 650 mg of Acetaminophen or 10 mg Oxycodone combined with 650 mg Acetaminophen. Patients were assessed at baseline, 30, 45 and 60 min. The primary outcome was reduction in pain at 60 min. Secondary outcomes include drug likeability and adverse events. RESULTS: 80 patients were enrolled in the study (40 per group). Demographic characteristics were similar between the groups (P > 0.05). Mean NRS pain scores at baseline were 8.44 for the MSIR group and 8.53 for the Percocet group (P = 0.788). Mean pain scores decreased over time but remained similar between the groups: 30 min (6.03 vs. 6.43; P = 0.453), 45 min (5.31 vs. 5.48; P = 0.779), and 60 min (4.22 vs. 4.87; P = 0.346). Reduction in mean NRS pain scores were statistically significant from baseline to 30, 45 and 60 min within each group (P < 0.0001 at each time point for both groups). The largest NRS mean difference was from baseline to 60 min: 4.2 (95% CI: 3.43 to 5.01) for MSIR group and 3.61 (95% CI: 2.79 to 4.43) for Percocet group. No clinically significant changes or any serious adverse events were observed in either group. CONCLUSION: MSIR provides similar analgesic efficacy as Percocet for short-term pain relief in the ED, similar rates of nausea/vomiting, and lower rates of likeability of the drug.

Nebulized Ketamine Used for Pain Management of Orthopedic Trauma.

BACKGROUND: Ketamine is a noncompetitive N-methyl-D-aspartate/glutamate receptor complex antagonist that decreases pain by diminishing central sensitization and hyperalgesia. When administered via i.v. (push-dose, short infusion, or continuous infusion) or intranasal routes, ketamine has shown to be effective in patients with acute traumatic pain. However, when i.v. access is not attainable or readily available, the inhalation route of ketamine administration via breath-actuated nebulizer (BAN) provides a noninvasive and titratable method of analgesic delivery. The use of nebulized ketamine has been studied in areas of postoperative management of sore throat and acute traumatic musculoskeletal and abdominal pain. To our knowledge, this is the first case series describing the use of nebulized ketamine for analgesia and orthopedic reduction. CASE SERIES: We describe 4 patients who presented to the emergency department with acute traumatic painful conditions (one patellar dislocation, one shoulder dislocation, and two forearm fractures) and received nebulized ketamine for management of their pain. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Administration of nebulized ketamine via BAN can be used as analgesic control for musculoskeletal trauma, as it can be administrated to patients with difficult i.v. access, has a rapid onset of analgesic effects with minimal side effects, and remains opioid-sparing.

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer's disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0-120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the "test" and "retest" data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

Social Interaction With an Alcohol-Intoxicated or Cocaine-Injected Peer Selectively Alters Social Behaviors and Drinking in Adolescent Male and Female Rats.

BACKGROUND: Drinking alcohol is facilitated by social interactions with peers, especially during adolescence. The importance of peer social influences during adolescence on alcohol and substance use has recently received more attention. We have shown that social interaction with an alcohol-intoxicated peer influences adolescent alcohol drinking differently in male and female rats using the demonstrator-observer paradigm. The present set of experiments analyzed the social interaction session to determine changes in social behaviors and subsequent alcohol drinking in adolescent male and female rats. METHODS: Specifically, in Experiment 1, we determined whether specific social behaviors were altered during interaction with an alcohol-intoxicated demonstrator administered 1.5 g/kg ethanol (EtOH) and assessed changes in EtOH intake in adolescent observers. Experiment 2 examined changes in voluntary saccharin consumption to determine whether social interaction with an alcohol-intoxicated demonstrator administered 1.5 g/kg EtOH altered consumption of a palatable solution. In Experiment 3, we administered saline, and a low (5 mg/kg) or high (20 mg/kg) dose of cocaine to the demonstrator and assessed changes in the adolescent observers to determine whether social interaction with a "drugged" peer altered social behaviors and voluntary EtOH intake. RESULTS: We showed that social interaction with an alcohol-intoxicated demonstrator administered 1.5 g/kg EtOH (i) decreased social play and increased social investigation and social contact in adolescent male and female observers, (ii) did not alter nonsocial behaviors, (iii) did not alter saccharin consumption, and (iv) increased voluntary EtOH intake in adolescent female but not male observers. When the peer was injected with cocaine, (i) social play was dose-dependently decreased, (ii) there were no changes in other social or nonsocial behaviors, and (iii) voluntary EtOH intake in adolescent male and female observers was unaffected. CONCLUSIONS: The present results are consistent and extend our previous work, showing that social interaction with an alcohol-intoxicated peer selectively alters social behaviors and alcohol drinking in adolescent rats. Females appear to be more sensitive to the elevating effects of social interaction on voluntary EtOH consumption.

Microbial translocation into amniotic fluid of vervet monkeys is common and unrelated to adverse infant outcomes.

Amniotic fluid was collected from pregnant female African green monkeys (n = 20). Analyses indicate microbial translocation into amniotic fluid during pregnancy is typical, and microbial load reduces across gestation. Microbial translocation does not relate to infant outcome or maternal factors. Lastly, we demonstrate that sample contamination is easily introduced and detectable.

Anatomical relationship of palmar carpal bone landmarks used in locating the lunate and capitate during palpation: A cadaveric investigation.

STUDY DESIGN: Descriptive in situ cadaveric study. INTRODUCTION: Performing accurately directed examination and treatment to the wrist requires clinicians to orient to carpal bone structures. PURPOSE OF THE STUDY: To examine the anatomical relationships that exist within the wrist-hand complex and identify the accuracy of surface anatomy mapping strategies for localizing anatomical landmarks using a palmar approach. METHODS: Twenty-three embalmed cadavers were dissected using standardized procedures. Metal markers were placed in the most prominent palmar landmark of key carpal structures. Relationships between the most prominent palpation landmarks and the carpal bones of interest were visualized using fluoroscopy. RESULTS: The most successful methods of palmar capitate localization included the midpoint of a line from trapezium tubercle to pisiform; the midpoint of a line from scaphoid tubercle to hamate hook; or the intersection (cross) of these 2 diagonal lines, with successful capitate identification 100% (23/23) of the time. The most successful method for locating the lunate included the midpoint of a line from the radial styloid process to the ulnar styloid process, which identified the lunate in 100% (23/23) of cases. DISCUSSION: The results of this cadaveric anatomical relationship study support the use of the midpoint of a line from pisiform to trapezium tubercle, the midpoint of a line from scaphoid tubercle to hamate hook, or a combination (cross) of these lines to locate the capitate from a palmar approach. In addition, the anatomical relationships examined in this study support the use of the midpoint of a line from the radial styloid process to ulnar styloid process to locate the lunate from a palmar approach. Knowledge of these anatomical relationships may improve the clinician's confidence in locating the capitate and lunate during intercarpal examination, special testing, and treatment. CONCLUSION: Results of this study provide information of the anatomical relationships of the carpal bones from a palmar approach, giving clinicians a foundation for proper orientation to the carpal bones during clinical examination and intervention. Further research is needed to evaluate the reliability and accuracy of these methods for surface palpation on live patients.

mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice.

Intestinal stem cells (ISCs) drive small intestinal epithelial homeostasis and regeneration. Mechanistic target of rapamycin (mTOR) regulates stem and progenitor cell metabolism and is frequently dysregulated in human disease, but its physiologic functions in the mammalian small intestinal epithelium remain poorly defined. We disrupted the genes mTOR, Rptor, Rictor, or both Rptor and Rictor in mouse ISCs, progenitors, and differentiated intestinal epithelial cells (IECs) using Villin-Cre. Mutant tissues and wild-type or heterozygous littermate controls were analyzed by histologic immunostaining, immunoblots, and proliferation assays. A total of 10 Gy irradiation was used to injure the intestinal epithelium and induce subsequent crypt regeneration. We report that mTOR supports absorptive enterocytes and secretory Paneth and goblet cell function while negatively regulating chromogranin A-positive enteroendocrine cell number. Through additional Rptor, Rictor, and Rptor/Rictor mutant mouse models, we identify mechanistic target of rapamycin complex 1 as the major IEC regulatory pathway, but mechanistic target of rapamycin complex 2 also contributes to ileal villus maintenance and goblet cell size. Homeostatic adult small intestinal crypt cell proliferation, survival, and canonical wingless-int (WNT) activity are not mTOR dependent, but Olfm4(+) ISC/progenitor population maintenance and crypt regeneration postinjury require mTOR. Overall, we conclude that mTOR regulates multiple IEC lineages and promotes stem and progenitor cell activity during intestinal epithelium repair postinjury.